The use of antibiotics in the treatment of infectious disease has increased greatly over the past fifty years. Due to the ubiquitous use, bacteria have developed resistance to the antibiotics commonly administered to treat bacterial infections. Antimicrobial resistance has been reported for all known antibacterial drugs currently available.
The global infectious disease treatment market is now over $100 billion, and by 2014 is expected to be $138 billion. According to the Centers for Disease Control and Prevention (CDC), each year in the US alone more than 2 million people acquire hospital-acquired infections (HAI) of which almost 100,000 die. Estimated costs associated with HAI in the US are as high as $30 billion annually. HAI and other infections are most often caused by gram-negative bacteria, but can also occur from other bacteria, viruses, fungi and parasites.
The annual cost of antibiotic-resistant infections in the US healthcare system has recently been calculated to be in excess of $20 billion. The widespread use of antibiotics, especially broad-spectrum antibiotics, is believed to have played a significant role in the emergence of resistant bacteria.
An effective delivery system for antimicrobials would target susceptible microorganisms rather than a systemic delivery to the entire body. This delivery system will allow for lower levels of the agents, reduce the exposure to beneficial organisms and minimize the development of drug-resistant strains of pathogens. The concept of a “magic bullet” delivery system has been widely discussed in the literature but, unfortunately, few strategies have proven successful. Drug activity is a result of molecular interaction(s) in certain cells. The drug must reach the cellular site of action at sufficient concentrations following oral, intravenous, local, transdermal, or other means of administration. The aim of drug delivery is to deliver the drug at the specific site of action, at the right concentration, and for the effective period of time.
One method that has been employed is the use of monoclonal antibodies with specificities directed toward specific antigenic sites on the targets. This presumes that antigenic sites on the targets can be defined and that for each pathogen unique antibodies can be produced that are directed toward these sites with minimal cross-reactivity. These goals are not easily achieved. Nonetheless, a system that can optimize cellular targeting, maintain effective intracellular antimicrobial concentrations and provide resistance to inhibit multiple targets within multiple classes of pathogens is a goal widely sought.
Gram negative bacterial pathogens constitute the most ubiquitous and serious sources of infection in civilian and military populations. Gram-negative bacteria have an outer membrane that protects them from antibiotics and detergents. All gram negative bacteria exhibit endotoxin or lipopolysaccharide (LPS) in their outer membrane. Endotoxin is composed of complex carbohydrates and a lipid. The carbohydrates vary in structure and confer the antigenic properties which distinguish different bacterial strains. The lipid is highly conserved across strains and is responsible for many of the pathogenic effects of endotoxin. Lipid A is the most common lipid moiety in gram negative bacteria and is a potent pyrogen and a polyclonal B lymphocyte activator. The ubiquitous nature of endotoxin makes it an attractive target for treatment of nearly all gram negative bacterial strains.
There exists a need for a pharmaceutical drug delivery system that can target specific cells and deliver treatment to the targeted cells.